This proposal describes the framework of a transitional grant for Alejandro B. Balazs, PhD. The grant would be activated after Dr. Balazs obtains an assistant professor position and would provide funding for the initial years of work. Dr. Balazs is currently a postdoctoral scholar in David Baltimore's laboratory at the California Institute of Technology. Dr. Balazs' research is focused on engineering the immune system via gene transfer as a novel means of creating protection against infectious disease in a process termed Vectored ImmunoProphylaxis (VIP). This proposal is focused on extending the recent demonstration of protection against HIV infection in humanized mice by monoclonal antibodies delivered by VIP. The proposal aims to extend these findings by determining the in vivo potency of several recently described broadly neutralizing antibodies that, in vitro, exhibited greater potency and breadth of neutralization than those described previously. It will study the potential for VIP to prevent infection by transmitted founder strains of HIV. It also aims to model human-to-human transmissions and determine the degree of protection against HIV infection conferred by VIP in a second humanized mouse model that exhibits greater immunological function. Finally, it will examine the contribution of escape mutations to the failure of VIP when expressing low concentrations of neutralizing antibodies. Together, this work will expand our understanding of the potential of using neutralizing antibodies delivered by gene transfer as prophylaxis against HIV, and it will explore viral escape, which might undermine the effectiveness of this and other vaccine approaches in humans.